It is well established that various organ allografts differ in their immunogenicity and susceptibility to immunosuppression-mediated acceptance. Lungs are among the most immunogenic organs with particularly high rates of graft rejection leading to poor long-term outcomes. Immunologic requirements for lung allograft rejection and acceptance remain poorly understood. Our laboratory has made the surprising observation that, in stark contrast to other organs, the presence of CD8+ (specifically CD8+PD-1+) rather than CD4+ T cells, is critical for co-stimulatory blockade-mediated acceptance of lung allografts. The overall goal of this application is to perform mechanistic studies in the mouse vascularized orthotopic lung transplantation model to investigate the role of CD8+ T cells in down-regulating alloimmune responses deleterious to graft survival. In the first aim we will define mechanisms of regulatory CD8+ T cell generation. In the second aim we will investigate the role of antigen presenting cells in CD8+ T cell-mediated lung allograft acceptance. In the third aim we will characterize how clinically relevant innate immune stimulation through Toll-like receptor 2 (TLR2) prevents CD8+ T cell-mediated lung allograft acceptance.